Plasmodium falciparum ATPase4 | Antimalarial targets | IUPHAR/BPS Guide to PHARMACOLOGY

Plasmodium falciparum ATPase4

Target id: 2971

Nomenclature: Plasmodium falciparum ATPase4

Abbreviated Name: PfATP4

Family: Antimalarial targets

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for Plasmodium falciparum ATPase4 in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Plasmodium falciparum 3D7 - 1264 ATP4 non-SERCA-type Ca2+ -transporting P-ATPase
Previous and Unofficial Names
P-type ATPase4
Database Links
UniProtKB
Whole Organism Assay Data Linked to This Target
Key to terms and symbols Click column headers to sort
Ligand Sp. Assay description Type Action Affinity Units Reference
(+)-SJ733 PfDd2 Parasite growth inhibition assay - - 7.7 pEC50 2
pEC50 7.7 (EC50 2x10-8 M) SYBR Green I assay [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
(+)-SJ733 Pf3D7 Parasite growth inhibition assay - - 7.5 pEC50 2
pEC50 7.5 (EC50 3x10-8 M) SYBR Green I assay [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
(+)-SJ733 PfK1 Parasite growth inhibition assay - - 7.4 pEC50 2
pEC50 7.4 (EC50 4x10-8 M) SYBR Green I assay [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
(+)-SJ733 PfV1/S Parasite growth inhibition assay - - 7.2 pEC50 2
pEC50 7.2 (EC50 6x10-8 M) SYBR Green I assay [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin PfNF54 Parasite growth inhibition assay - - 9.3 pIC50 3
pIC50 9.3 (IC50 5x10-10 M) [3H]-hypoxanthine incorporation assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin PfTM90C2A Parasite growth inhibition assay - - 9.3 pIC50 3
pIC50 9.3 (IC50 5x10-10 M) [3H]-hypoxanthine incorporation assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin PfK1 Parasite growth inhibition assay - - 9.2 pIC50 3
pIC50 9.2 (IC50 6x10-10 M) [3H]-hypoxanthine incorporation assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin Pf3D7 Parasite growth inhibition assay - - 9.1 pIC50 3
pIC50 9.1 (IC50 7x10-10 M) [3H]-hypoxanthine incorporation assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin PfW2 Parasite growth inhibition assay - - 9.1 pIC50 3
pIC50 9.1 (IC50 9x10-10 M) [3H]-hypoxanthine incorporation assay [3]
cipargamin PfTM91C235 Parasite growth inhibition assay - - 9.1 pIC50 3
pIC50 9.1 (IC50 9x10-10 M) [3H]-hypoxanthine incorporation assay [3]
cipargamin PfD6 Parasite growth inhibition assay - - 9.0 pIC50 3
pIC50 9.0 (IC50 1x10-9 M) [3H]-hypoxanthine incorporation assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin Pf7G8 Parasite growth inhibition assay - - 8.9 pIC50 3
pIC50 8.9 (IC50 1.2x10-9 M) [3H]-hypoxanthine incorporation assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin PfV1/S Parasite growth inhibition assay - - 8.9 pIC50 3
pIC50 8.9 (IC50 1.4x10-9 M) [3H]-hypoxanthine incorporation assay [3]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
cipargamin PfNF54 Parasite early stage (I–II) gametocyte assay - - - - 5
Giemsa-stained blood film counts: dose-dependent, significant inhibition of stage II gametocyte development [5]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
cipargamin PfNF54 Parasite late stage (III–V) gametocyte assay - - - - 5
Giemsa-stained blood film counts: dose-dependent, inhibition of stage V gametocyte development [5]
Lifecycle stages: Plasmodium sexual blood stage (gametocyte)
cipargamin PfNF54 Standard membrane feeding assay (SMFA) - - - - 5
Oocyst count: significantly reduced count observed with the addition of cipargamin when compared to control feeds [5]
Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)
General Comments
Mutations in PfATP4 have been shown to confer resistance by the Plasmodium parasite to the activity of a chemically diverse range of antimalarial drug candidates, including the spiroindolones, the dihydroisoquinolones and the aminopyrazoles [1-3]. Exposure of the parasite to these drug classes disrupts Na+ regulation [2,4], with the maintenance of a low cytosolic Na+ concentration essential for parasite survival during the intraerythrocytic stages of development. The exact interaction and mechanism by which these compounds lead to parasite death have not been fully elucidated, but host-mediated clearance of infected erythrocytes may be responsible for the rapid action of PfATP4 inhibitors [2].

References

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1. Flannery EL, McNamara CW, Kim SW, Kato TS, Li F, Teng CH, Gagaring K, Manary MJ, Barboa R, Meister S et al.. (2015) Mutations in the P-type cation-transporter ATPase 4, PfATP4, mediate resistance to both aminopyrazole and spiroindolone antimalarials. ACS Chem. Biol., 10 (2): 413-20. [PMID:25322084]

2. Jiménez-Díaz MB, Ebert D, Salinas Y, Pradhan A, Lehane AM, Myrand-Lapierre ME, O'Loughlin KG, Shackleford DM, Justino de Almeida M, Carrillo AK et al.. (2014) (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium. Proc. Natl. Acad. Sci. U.S.A., 111 (50): E5455-62. [PMID:25453091]

3. Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J et al.. (2010) Spiroindolones, a potent compound class for the treatment of malaria. Science, 329 (5996): 1175-80. [PMID:20813948]

4. Spillman NJ, Allen RJ, McNamara CW, Yeung BK, Winzeler EA, Diagana TT, Kirk K. (2013) Na(+) regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials. Cell Host Microbe, 13 (2): 227-37. [PMID:23414762]

5. van Pelt-Koops JC, Pett HE, Graumans W, van der Vegte-Bolmer M, van Gemert GJ, Rottmann M, Yeung BK, Diagana TT, Sauerwein RW. (2012) The spiroindolone drug candidate NITD609 potently inhibits gametocytogenesis and blocks Plasmodium falciparum transmission to anopheles mosquito vector. Antimicrob. Agents Chemother., 56 (7): 3544-8. [PMID:22508309]

How to cite this page

Antimalarial targets: Plasmodium falciparum ATPase4. Last modified on 12/09/2018. Accessed on 15/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2971.